Podcast: The Role of T-Lymphocytes in Glioma Pathobiology
Dr. Iyad Alnahhas (Jefferson University Neuro-Oncology) interviews pediatric brain cancer pioneer Dr. David Gutmann (Washington University - St. Louis) about his recent Neuro-Oncology review paper
Left Panel: David H. Gutmann, MD, PhD; Right Panel: Iyad Alnahhas, MD, MS
Looking for a concise overview of the multi-faceted role of T-lymphocytes in glioma brain tumors? Recommend that you check out this podcast from the Society for Neuro-Oncology. Dr. Iyad Alnahhas of the Brain Tumor Center at Thomas Jefferson University Hospitals interviews Dr. David H. Gutmann, pediatric brain tumor research pioneer. Dr. Gutmann’s recently published review outlining the multiplex role of T-lymphocytes in gliomas is always near the top of our reading list.
Brain tumors often display complex, heterogenous Tumor Micro-Environments (TME) with various cellular populations represented. A central challenge in effectively deploying modern Immuno-Oncology (I/O) agents against brain tumors has been the complicated and dynamic spectrum of immunologically active cells in the TME. The most promising therapeutic approaches encourage cytotoxic T-lymphocytes (CTLs) to traffic to the tumor in order to kill the tumor cells. However, cancer is a clever beast, and deploys overlapping layers of defense mechanisms to thwart CTL attack. Tumor cells often display immune checkpoint ligands (e.g. PD-L1, LAG-3, etc) to both degrade CTL traffic and exhaust the CTLs that make it into the TME. In addition, myeloid-derived suppressor cells (MDSCs; macrophages, monocytes, etc) have been observed to make up a large portion of the total cell mass in certain TMEs. MDSCs work to further abrogate CTL attack by secreting cytokines, chemokines and other “Don’t Eat Me” molecular signals.
Given the dynamic and immune-suppressive ballet of the TME, what is the best way to enable CTLs to hammer the tumor cells?
Multiple lines of independent research are beginning to converge on an attractive Central Hypothesis to guide the design of clinical therapeutic regimens:
Deploy a “Perturbation” to transform the TME from a “Cold” immune-suppressed environment to a “Hot” immune-attractive environment.
Treat with I/O agents that encourage non-exhausted CTL traffic into the TME (e.g. checkpoint inhibitors like pembrolizumab or nivolumab)
If possible, also treat with agents that reduce the immune-suppressive effects of MDSCs.
Recent data suggests that several different approaches can be used as the Perturbation (e.g. Tumor Treating Fields, DNA damage agents, Radiation, Vaccines, Oncolytic viruses with immune-active warheads). I will cover this topic in more detail in an upcoming post.
However, one thing is becoming increasingly clear: Failure to transform the TME from Cold to Hot will significantly reduce the effectiveness of the best I/O agents. This phenomenon has recently been recognized as the likely reason why early I/O clinical studies in GBM failed to yield adequate objective tumor responses.
When we were designing Julie’s customized GBM therapeutic regimen, we invoked the Central Hypothesis to select:
Tumor Treating Fields (Novocure) as the Perturbation
Pembrolizumab (Merck) as the anti-PD-1 I/O agent
Infliximab (Janssen) as a necessary prophylactic agent to prevent neutrophil-driven, innate immune system attack on non-tumor tissues
The clinical results have been remarkable to date.
On a personal note, Dr. Alnahhas is a pivotal member of #TeamJulie, and has provided exceptional care and clinical case management over the past year working in concert with Julie’s global team. We cannot thank him enough.
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